Indazole compounds useful as ketohexokinase inhibitors

Abstract

The present invention is directed to substituted indazole compounds, pharmaceutical compositions of these compounds and methods of use thereof. The compounds of the present invention are ketohexokinase (KHK) inhibitors, useful for treating or ameliorating a KHK mediated metabolic disorders and/or diseases such as obesity, Type II diabetes mellitus and Metabolic Syndrome X. In some embodiments, the substituted indazole compounds are of formula I, wherein R 1 -R 3 , Q, X, Y, Z, a, and b are defined herein.

What is claimed: 
     
       1. A compound selected from the group consisting of:
 6-(4-azetidin-3-yl-piperazin-1-yl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine, 
 3-ethyl-1-phenyl-6-(4-(pyridin-3-yl)piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetic acid, 
 3-methyl-1-phenyl-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol, 
 6-(1-azetidin-3-yl-piperidin-3-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol, 
 3-methyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride, 
 [4-(4-hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-piperidin-1-yl]-piperidin-4-yl-methanone hydrochloride, 
 3-methyl-1-phenyl-6-(1-pyrrolidin-3-yl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride, 
 6-[1,4′]bipiperidinyl-4-yl-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride, 
 6-(1-azetidin-3-yl-piperidin-4-ylmethyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol, 
 3-ethyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride, 
 3-ethyl-1-phenyl-6-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol, 
 3-ethyl-1-phenyl-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol, 
 3-ethyl-1-phenyl-6-(1-pyrrolidin-3-yl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride, 
 6-[1,4′]bipiperidinyl-4-yl-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride, and 
 [4-(3-ethyl-4-hydroxy-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-piperidin-1-yl]-piperidin-4-yl-methanone hydrochloride. 
 
     
     
       2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
       3. A compound which is 3-ethyl-1-phenyl-6-(4-(pyridin-3-yl)piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetic acid. 
     
     
       4. A process for making a pharmaceutical composition comprising mixing a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       5. A pharmaceutical composition comprising a compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
       6. A process for making a pharmaceutical composition comprising mixing a compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
       7. A method of treating a disorder selected from the group consisting of obesity, elevated glucose levels, glucose intolerance, insulin resistance, Type I diabetes mellitus, Type II diabetes mellitus, Metabolic Syndrome X, elevated triglycerides, hyperlipidemia and hypertension, comprising administering to a subject having said disorder a therapeutically effective amount of the compound of  claim 1 ;
 wherein said treating includes alleviating a symptom or complication of said disorder, eliminating said disorder, reducing the frequency of one or more symptoms of said disorder, reducing the severity of one or more symptoms of said disorder, delaying the development of an additional symptom of said disorder, or delaying the development of said disorder. 
 
     
     
       8. The method of  claim 7 , wherein the disorder is selected from the group consisting of obesity, Type II diabetes mellitus and Metabolic Syndrome X. 
     
     
       9. A method of treating a condition selected from the group consisting of obesity, elevated glucose levels, glucose intolerance, insulin resistance, Type I diabetes mellitus, Type II diabetes mellitus, Metabolic Syndrome X, elevated triglycerides, hyperlipidemia and hypertension comprising administering to a subject having said condition a therapeutically effective amount of the composition of  claim 2 ;
 wherein said treating includes alleviating a symptom or complication of said condition, eliminating said condition, reducing the frequency of one or more symptoms of said condition, reducing the severity of one or more symptoms of said condition, delaying the development of an additional symptom of said condition, or delaying the development of said condition. 
 
     
     
       10. A method of treating a condition selected from the group consisting of obesity, elevated glucose levels, glucose intolerance, insulin resistance, Type I diabetes mellitus, Type II diabetes mellitus, Metabolic Syndrome X, elevated triglycerides, hyperlipidemia and hypertension comprising administering to a subject having said condition a therapeutically effective amount of the compound of  claim 3 ;
 wherein said treating includes alleviating a symptom or complication of said condition, eliminating said condition, reducing the frequency of one or more symptoms of said condition, reducing the severity of one or more symptoms of said condition, delaying the development of an additional symptom of said condition, or delaying the development of said condition. 
 
     
     
       11. A method of treating a condition selected from the group consisting of obesity, elevated glucose levels, glucose intolerance, insulin resistance, Type I diabetes mellitus, Type II diabetes mellitus, Metabolic Syndrome X, elevated triglycerides, hyperlipidemia and hypertension comprising administering to a subject having said condition a therapeutically effective amount of the composition of  claim 5 ;
 wherein said treating includes alleviating a symptom or complication of said condition, eliminating said condition, reducing the frequency of one or more symptoms of said condition, reducing the severity of one or more symptoms of said condition, 
 delaying the development of an additional symptom of said condition, or delaying the development of said condition. 
 
     
     
       12. The method of  claim 10 , wherein the condition is selected from the group consisting of obesity, Type II diabetes mellitus and Metabolic Syndrome X.